Cystic Fibrosis (CF), the most common lethal genetic disease in the Caucasian population, results from mutations in the CFTR gene and affects the epithelia of multiple organs including the lung and gastrointestinal tract. Multiple research strategies for treatment of CF are currently being explored. Translating CF therapeutic strategies from basic research to clinical studies requires the assessment of drug candidates in physiologically relevant assays that require specific expertise. To support urgently required translational CF research, the Pre- Clinical Core (Core B) of the University of North Carolina CF Research and Translation Core Center will pursue three Specific Aims: Specific Aim 1 will evaluate pre-clinical drug candidates in vitro in primary human airway and intestinal planar epithelial CF cultures by measurement of ion transport, CFTR maturation and surface expression, drug pharmacokinetics, and airway surface liquid properties. Specific Aim 2 will focus on evaluation of pre-clinical drug candidates ex vivo in organoid models (i.e. colonospheres, nasospheres, and bronchospheres) and various epithelial tissues (mouse distal colon, jejunum, gallbladder, trachea, bronchi, and nasopharnyx, and human rectal biopsies). Services provided are quantitative organoid swelling assays, functional assessment of ion transport in tissues, and biochemical assessment of CFTR rescue in organoids and tissues. Specific Aim 3 will evaluate pre-clinical drug candidates in vivo in relevant mouse models of CF and other lung diseases using a variety of assays to determine the efficacy of therapeutic treatments on ion transport defects, CFTR processing, defective mucus clearance, chronic infection, and inflammation. Services provided in this Aim include mouse maintenance and distribution, pharmacological treatments, pharmacokinetic analyses, and phenotyping including collection of bronchoalveolar lavage, measurements of soluble mediators, airway mucus burden and clearance, nasal PD, salivary secretion rates, histopathology, morphometry, microbiology, and state-of-the art airway imaging. While certain assays and models provided by the Core focus on restoration of CFTR function in CF, most of our services have broad applications to multiple research programs seeking therapeutic benefit for CF. These include approaches that utilize small-molecule pharmacological interventions, gene therapy, correction of airway surface liquid hydration and mucus clearance defects, normalization of ion transport, and inflammation/infection control. The availability of these models and assays will provide a translational bridge that will support the rapid transfer of emerging drug candidates to CF therapy.